The role of interleukin-25-producing T-helper-cells during colitis-associated and spontaneous colon tumorigenesis

产生白细胞介素 25 的 T 辅助细胞在结肠炎相关和自发性结肠肿瘤发生中的作用

• 批准号: 259317850
• 负责人: Professor Dr. Stefan Fichtner-Feigl
• 金额: --
• 依托单位: Klinik für Allgemein- und Viszeralchirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/259317850?language=en
• 关键词: role; interleukin; 25; producing; helper

Colorectal cancer is a common and malignant disease that includes various subtypes and their therapeutic options are still insufficient. Interleukin-25 is a cytokine of the interleukin-17 family and plays a central role in the intestinal immune homeostasis and defense against infection. In addition to intestinal epithelial cells, the known source of interleukin-25, we can now demonstrate the existence of interleukin-25-producing T helper cells in the intestine. Several indicators, including our own preliminary work suggest a pathological significance of this new line of T-cell differentiation in the development of colorectal carcinomas. The aim of the project is to highlight the importance of interleukin-25-producing T helper cells for intestinal tumorigenesis in detail. In the center of this proposal are in vivo experiments with well-established experimental models and the molecular analysis of intestinal tumorigenesis. This project is subject to the following hypotheses : 1) Th25 cells initiate IL-13+ NKT-cell-mediated murine ulcerative colitis and support colitis-associated tumor progression. The differentiation of IL-13+ NKT-cells is mainly induced by Th25 cells (not by IL-25-producing epithelial cells). 2) Tumor-infiltrating Th25 cells mediate an immunological tumor control via granzyme B and perforin and suppress the progression of spontaneous colon tumors. The project will answer the following questions: 1) Does the absence of interleukin-25-producing lymphocytes affect intestinal barrier function or bacterial translocation in the colon? 2) Is there a different distribution pattern of Th25 cells (in particular tumor-infiltrating Th25 cells) and can an alteration of granzyme B and perforin expression be detected during colitis-associated and spontaneous colon tumorigenesis? 3) Are Th25 cells necessary for the chronic oxazolone colitis in the AOM-oxazolone tumor model and are Th25 cells pro-tumorigenic or outweighs their cytotoxic activity against tumor cells? 4) Does secreted IL-25 mediate its effects mainly on immune cells via modification of the inflammatory response or directly on IL-17RB+ intestinal epithelial/tumor cells? 5 ) Is there a correlation of the infiltration by Th25 cells with the local inflammatory activity in human ulcerative colitis and with tumor stage of patients with sporadic colorectal cancer? Are there any molecular differences between Th25 cells isolated from human ulcerative colitis or sporadic colorectal cancer? The target of this project thus is to examine the role of interleukin-25-producing T helper cells in the formation and growth of colorectal cancer and explore potential opportunities for intervention in this immunological cascade.

结直肠癌是一种常见的恶性疾病，包括多种亚型，治疗选择仍然不足。 Interleukin-25 是 IL-17 家族的一种细胞因子，在肠道免疫稳态和防御感染中发挥着核心作用。除了肠上皮细胞（白细胞介素 25 的已知来源）之外，我们现在还可以证明肠道中存在产生白细胞介素 25 的 T 辅助细胞。包括我们自己的前期工作在内的多项指标表明，这种新的 T 细胞分化系在结直肠癌的发展中具有病理学意义。该项目的目的是详细强调产生白细胞介素 25 的 T 辅助细胞对肠道肿瘤发生的重要性。该提案的核心是利用完善的实验模型进行体内实验以及肠道肿瘤发生的分子分析。该项目遵循以下假设：1) Th25 细胞引发 IL-13+ NKT 细胞介导的小鼠溃疡性结肠炎并支持结肠炎相关的肿瘤进展。 IL-13+ NKT 细胞的分化主要由 Th25 细胞（而不是产生 IL-25 的上皮细胞）诱导。 2) 肿瘤浸润 Th25 细胞通过颗粒酶 B 和穿孔素介导免疫肿瘤控制，并抑制自发性结肠肿瘤的进展。该项目将回答以下问题：1）产生白细胞介素25的淋巴细胞的缺乏是否会影响肠道屏障功能或结肠中的细菌易位？ 2）Th25细胞（特别是肿瘤浸润性Th25细胞）是否存在不同的分布模式？在结肠炎相关和自发性结肠肿瘤发生过程中能否检测到颗粒酶B和穿孔素表达的改变？ 3) Th25细胞是AOM-恶唑酮肿瘤模型中慢性恶唑酮结肠炎所必需的吗？Th25细胞是否具有促肿瘤性或超过其对肿瘤细胞的细胞毒活性？ 4) 分泌的 IL-25 是否主要通过改变炎症反应来介导其对免疫细胞的影响，还是直接对 IL-17RB+ 肠上皮/肿瘤细胞产生影响？ 5）Th25细胞浸润与人类溃疡性结肠炎局部炎症活动以及散发性结直肠癌患者的肿瘤分期是否存在相关性？从人类溃疡性结肠炎或散发性结直肠癌中分离的 Th25 细胞之间是否存在分子差异？因此，该项目的目标是检查产生白介素 25 的 T 辅助细胞在结直肠癌形成和生长中的作用，并探索干预这一免疫级联的潜在机会。